Estacion M, Dib-Hajj S D, Benke P J, Te Morsche Rene H M, Eastman E M, Macala L J, Drenth J P H, Waxman S G
Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
J Neurosci. 2008 Oct 22;28(43):11079-88. doi: 10.1523/JNEUROSCI.3443-08.2008.
Gain-of-function mutations of Na(V)1.7 have been shown to produce two distinct disorders: Na(V)1.7 mutations that enhance activation produce inherited erythromelalgia (IEM), characterized by burning pain in the extremities; Na(V)1.7 mutations that impair inactivation produce a different, nonoverlapping syndrome, paroxysmal extreme pain disorder (PEPD), characterized by rectal, periocular, and perimandibular pain. Here we report a novel Na(V)1.7 mutation associated with a mixed clinical phenotype with characteristics of IEM and PEPD, with an alanine 1632 substitution by glutamate (A1632E) in domain IV S4-S5 linker. Patch-clamp analysis shows that A1632E produces changes in channel function seen in both IEM and PEPD mutations: A1632E hyperpolarizes (-7 mV) the voltage dependence of activation, slows deactivation, and enhances ramp responses, as observed in Na(V)1.7 mutations that produce IEM. A1632E depolarizes (+17mV) the voltage dependence of fast inactivation, slows fast inactivation, and prevents full inactivation, resulting in persistent inward currents similar to PEPD mutations. Using current clamp, we show that A1632E renders dorsal root ganglion (DRG) and trigeminal ganglion neurons hyperexcitable. These results demonstrate a Na(V)1.7 mutant with biophysical characteristics common to PEPD (impaired fast inactivation) and IEM (hyperpolarized activation, slow deactivation, and enhanced ramp currents) associated with a clinical phenotype with characteristics of both IEM and PEPD and show that this mutation renders DRG and trigeminal ganglion neurons hyperexcitable. These observations indicate that IEM and PEPD mutants are part of a physiological continuum that can produce a continuum of clinical phenotypes.
已证明，电压门控性钠通道1.7（Na(V)1.7）的功能获得性突变会引发两种截然不同的疾病：增强激活作用的Na(V)1.7突变会导致遗传性红斑性肢痛症（IEM），其特征为四肢灼痛；而损害失活作用的Na(V)1.7突变则会引发一种不同的、不重叠的综合征——阵发性极端疼痛障碍（PEPD），其特征为直肠、眼周和下颌周围疼痛。在此，我们报告了一种与兼具IEM和PEPD特征的混合临床表型相关的新型Na(V)1.7突变，该突变发生在结构域IV的S4-S5连接子中，导致丙氨酸1632被谷氨酸取代（A1632E）。膜片钳分析表明，A1632E产生了在IEM和PEPD突变中均可见的通道功能变化：A1632E使激活的电压依赖性超极化（-7 mV），减缓失活过程，并增强斜坡电流响应，这与产生IEM的Na(V)1.7突变情况一致。A1632E使快速失活的电压依赖性去极化（+17 mV），减缓快速失活过程，并阻止完全失活，从而导致类似于PEPD突变的持续性内向电流。运用电流钳技术，我们发现A1632E使背根神经节（DRG）和三叉神经节神经元兴奋性增高。这些结果表明，存在一种具有PEPD（快速失活受损）和IEM（超极化激活、缓慢失活以及增强的斜坡电流）共同生物物理特征的Na(V)1.7突变体，它与兼具IEM和PEPD特征的临床表型相关，并且表明该突变使DRG和三叉神经节神经元兴奋性增高。这些观察结果表明，IEM和PEPD突变体属于一个生理连续体的一部分，该连续体能够产生一系列连续的临床表型。
